Oxycodone and oxymorphone are opioid analgesic medications synthesized from opium-derived thebaine or oripavine. 14-hydroxycodeinone and 14-hydroxymorphinone are the immediate precursors to oxycodone or oxymorphone in these syntheses. 14-hydroxycodeinone and 14-hydroxymorphinone belong to a class of compounds known as α,β-unsaturated ketones. These compounds have been designated as potential gene-toxins due to their susceptibility to the Michael addition reaction.
The following reaction scheme shows the conversion of thebaine to oxycodone via the intermediate 14-hydroxycodeinone.

Oxymorphone can be produced by oxidation of oripavine, followed by reduction of the intermediate, as illustrated in the following scheme:

Oxycodone can be manufactured from thebaine by a process as disclosed for example in U.S. Pat. No. 6,090,943 B (Exp.8). Thebaine or a salt thereof is reacted with hydrogen peroxide in isopropanol, water and formic acid, producing 14-hydroxy-codeinone. The double bond in the 14-hydroxycodeinone is reduced by reaction with hydrogen in the presence of a Pd/BaSO4 catalyst, providing oxycodone.
The International Patent Application WO 2008/130553 (Mallinckrodt Inc.) discloses an oxidation step of oripavine, said step comprising the in-situ formation of at least one peroxyacid. Moreover, the application discloses a reduction of the intermediate to form oxymorphone, utilizing catalytic hydrogen transfer reagent.
The International Patent Application WO 2008/048711 (Penick Corporation) describes a method of preparing oxymorphone from oripavine, including converting oripavine to 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone.
U.S. Pat. No. 7,153,966 B (Johnson Matthey Public Limited) describes a method for the preparation of oxycodone from thebaine having low levels of impurities, such as 14-hydroxy-codeinone. According to said patent the pH must be adjusted before the hydrogenation step in order to achieve low levels of 14-hydroxycodeinone.
U.S. Pat. No. 7,071,336 B (Acura Pharmaceuticals) discloses a process for the preparation of oxycodone, which comprises the steps of oxidation of a composition including a thebaine component into 14-hydroxycodeinone, and reduction of 14-hydroxycodeinone to oxycodone, wherein the composition including the thebaine component comprises a concentrate of poppy straw.
U.S. Pat. No. 7,129,248 B (Euro-Celtique, S.A.) discloses a process for preparing an oxycodone hydrochloride composition having less than 25 ppm 14-hydroxycodeinone comprising hydrogenating an oxycodone hydrochloride composition having at least 100 ppm 14-hydroxycodeinone in a suitable solvent to produce an oxycodone composition having less than 25 ppm 14-hydroxycodeinone.
EP 1 658 293 B (Zentiva, A.S.) discloses a method of preparation of oxycodone by reaction of thebaine with hydrogen peroxide or peroxoacids in the presence of oxalic acid and of another organic acid. To the resulting crystalline precipitate of 14-hydroxy-codeinone oxalate is added a base to form 14-hydroxycodeinone, which is hydrogenated with hydrogen in the presence of a catalyst to yield oxycodone.
EP 1 861 405 B (Euro-Celtique S.A.) discloses a process for reducing the amount of α,β-unsaturated ketone in an opioid analgesic composition comprising hydrogenating a starting opioid analgesic composition having an α,β-unsaturated ketone impurity with diimide, a diimide progenitor, or a combination thereof in a suitable solvent.
The International Patent Application WO 2008/070658 (Noramco Inc.) discloses a process for preparing oxycodone and oxycodone HCl with low levels of 14-hydroxycodeinone, comprising heating the mixture of oxycodone (HCl) and a sulfite compound in an alcohol/water solvent under basic conditions and isolating said oxycodone (HCl).
The International Patent Application WO 2009/004491 (Alpharma APS) discloses a one-pot process for the preparation of oxycodone from thebaine which comprises (i) oxidation of thebaine to 14-hydroxycodeinone with a peroxide; and (ii) reduction of 14-hydroxycodeinone with hydrogen, characterised in that: (iii) the oxidation reaction is carried out on more than 50 g of thebaine, and (iv) both the oxidation and reduction reactions are carried out in acetic acid or propionic acid; and (v) both the oxidation and reduction reactions are carried out in the same vessel without isolation of the 14-hydroxycodeinone; and (vi) the oxidation reaction is performed at a temperature below 35° C.
However, all the cited processes are complicated and time consuming. Therefore, there is still a need to improve the process for preparing opiates having low levels of impurities.